Preparation of thienyl amido-1,3-propanediols



PREPARATIQN (E F THHENYL AMEN)- LE-PRQPANEDKOLS Edward C. Hermann,Wilmington, DeL, assiguor to E. I. du Pont de Nemours and Company,Wilmington, Del., a corporation of Delaware No Drawing. ApplicationAugust 23, 1951, Serial No. 243,361

Claims. (Cl. 260-3322) This invention relates to the preparation ofthienyl amido-1,3-propanediols.

This application is a continuation-in-part of my copending applicationSerial No. 172,393, filed July 6, 1950, now abandoned.

The thienylamido-1,3-propanediols prepared by the processes of theinvention are represented by the formula where R1 represents hydrogen ora lower allryl radical R2 is hydrogen, halogen, nitro, or a lower alkylradical and acyl represents a radical such as saturated lower ali- 1phatic acyi, halogen substituted lower aliphatic acyl, ether substitutedlower aliphatic acyl, hydroxy substituted lower aliphatic acyl,substituted and unsubstituted alieyclic acyl, heterocyclic acyl andaromatic acyl. The term lower alkyl as used herein includes all alkylradicals containing not more than 6 carbon atoms. r Illustrative ofthienyl amido-1,3-propanediols prepared by the processes of theinvention are:

l-(5-nitro-2-thienyl)-2-dichloroacetamido 1,3 propanediol l-5-bromo-2-thienyl -2 dichloroacetamido-1,3-propanediol l-S-chloro-Z-thienyl -2-dichloroacetamido 1,3-propanediol 1- Z-thienyl-2-dichloroacetamido- 1 ,3-propanediol1-(5methyl-2thienyl)-2-dichloroacetamido 1,3-propanediol1-(S-ethyl-Z-thienyl)-2-dichloroacetarnido 1,3 propane-1-(S-heXyl-Z-thienyl)-2-diehloroacetamido 1,3 propanediol1-(3-methyl-5-nitro-2-thienyl)-2-dichloroacetamido 1,3-

propanediol 1-(S-nitro-Z-thienyl)-2-acetamido-1,3-propanediol 2,? Hi i lFatented July 2 3, 1955 "ice The compounds of the, invention areprepared from previously known organic compounds by novel syntheseswhich I have discovered. These processes involve the preparation of anumber of intermediate organic compounds, the existence of .which hasnot heretofore been known.

Certain of these new intermediate compounds and all of the compoundsrepresented by the above formula may exist in optical isomeric forms.The stereoisomeric forms as used herein refer to the spatial arrangementof the polar groups on the two asymmetric carbon atoms with reference toerythrose and threose. To differentiate between these two possible formsI will subsequently refer to the pair of stereoisomers related toerythrose in configuration as the A series or form and the pair ofstereoisomers related to threose as the B series or form.

Both the A and the B forms-exist as racemates of optically active dextro(d) and levo (l) rotatory isomers as well as in the form of theindividual or separated dextro (d) and levo (1) optical isomers.

in view of the difiiculty of representing the various optical isomerswith plane formulas, I have used the customary structural formulas andadopted the following convention in order to designate their opticalconfiguration. Where the formula represents a specific opticalconfiguration( s) I will use an appropriate notation under the formula,for example (l)-B form, (d)-A form, (db-B form and the like.

It will be understood that where no notation appears with a structuralformula or with a chemical name the formula or name is to be interpretedin its generic sense; that is, as representing the (l)B, (d)-B, (l)-A,or (d)-A isomers in separated form as well as the (dl)-B or the (db-Aoptical racernates or a mixture of the unresolved diastereoisomers. Inother words, a formula or name represents not only the unresolvedmixture of isomers, but also the individual isomers and racemates.

Using the above conventions, one of the methods provided for theproduction of the thienyl amide-1,3-

propanediols in accordance with my invention can be diagrammaticallyrepresented as follows: Step1 R1 1 '1 R \S o XOO CH2? (a) (b)\cetylationr r I O Halogenation O l I l i 1 R s ,C-CH2X R2- S --CH3(e)\Hexamethylene \tetramine R \l OHz--N t Rz\s -CHzNCHz-N\ CHQX- CH2- NStep2 lHCl I! I R2\ -CHzNlEh-HCI Base Acylation Weaki Step 4 Base L l onlTlH-Acyl 'R2 S oH-oH-omon Tertiary l Acylation Amine Step 6 R1 I 1 i onlTlH-Acyl R CHGHCH2OH where R1 and R2 have the same significance asgiven above and X represents a chloro or bromo radical.

Step 1 of my general process involves converting a thiophene compound ofthe formula to a hexamethylenetetrarninium halide of formula CH2N Thiscan be accomplished in several different ways as will be apparentbyreference to Step 1 of the above diagram.

The choice of one of the above methods depends upon a number of factorsbut primarily upon the nature of substituents on the thiophene nucleus.The shorter procedure involving sub-steps (a) and (e) is particularlypreferred where R1 and/ or R2 are alkyl. In sub-step (a) the preferredacetylating agentis bromoacetyl bromide.

The next step of the process, Step 2, comprises hydrolyzing thequaternary ammonium salt produced in Step 1 with a mineral acid such as,for instance, hydrochloric,

.uti

iii)

phosphoric or sulfuric acid. The acid salt of an amine,

for example,

R1 I 0 l R S C H2NH2-H Cl is obtained. It is preferred to carry out thehydrolysis in the presence of an alcohol.

Step 3 comprises N-acylating the (2-thenoylmethyl)- amine hydrochloridecompound obtained in Step 2. This is preferably accomplished by use ofacetic anhydride in the presence of a weak base, such as, for instance,sodium acetate, at temperatures below C. In those instances where R1 andR2 are hydrogen, it has been found particularly advantageous to employdichloroacetyl chloride or similar acid halides in place of aceticanhydride.

The fourth step in the process involves an aldol type of condensation,whereby the amide derivative produced in Step 3 is converted tocompounds of formula I?! o NH-Acyl n \s ii-(3HCH2OH This is preferablycarried out in a dilute alkaline medium such as, for instance, anaqueous sodium bicarbonate solution, using an aqueous formaldehydesolution of 3638% concentration.

Step 5, the next step of my process, involves a reduction of thecarbonyl group of the compound produced in Step 4 to a hydroxyl group.This reduction can be carried out in excellent yields using sodiumborohydride in comparatively short periods of time, say, for instance,one half hour. It is preferred to use an alcoholic medium in order tosolubilize the reactants. For optimum results the temperature of thereaction mixture should be maintained at from about to C.

If desired, the two diastereoisomeric pairs, forms A and B, can beseparated at this stage. Separation can usually be effected quitecompletely by utilizing the difierence in solubility of the two forms inorganic solvents, such as, for instance, ethyl acetate or diOXane.However, in some instances, the solvent solubility differential of thetwo forms is not great enough to aflord a clean-cut separation of thetwo structural isomers. In such situations it is preferable to acylatethe product of Step 5 in accordance with Step 6.

Step 6 of my general process involves converting thel-(Z-thienyl)-2-amido-1,3-propanediol type compound produced in Step 5to the completely acylated amino diol. The conversion can be carried outin two different Ways. Mono-acylation followed by complete acylation maybe employed. Alternatively, diacylation may be carried out in one step.I prefer to carry out the complete acylation of the thienyl amino diolin a single step rather than in two steps.

The complete acylation of the product obtained in Step 5 can beaccomplished by treatment of the thienyl amido diol compound with anacylating agent, preferably acetic anhydride, in the presence of aninorganic or tertiary organic base under substantially anhydrousconditions. In general, this transformation can be effected by heatingthe reaction mixture at a temperature of from about to C. for a periodfrom, say, about 15 minutes to several hours.

Any of a wide variety of tertiary bases may be used with the acylatingagent. There may be used, for instance, pyridine, quinoline,dimethylaniline, triethylamine, N- ethylpiperidine and the like.

Where one particular diastereoisomeric pair of the product is sought,separation of the A and B forms can be effected at this point. The twodiastereoisomeric pairs of the triacetyl derivative differ in theirsolubility in alcohol. A separation of the two diastereoisomeric pairscan, for instance, be carried out by repeated crystallizations fromethanol. I

It is preferred to separate these diastereoisomeric ans by hydrolyzingthe mixture of the triacetyl derivatives to the correspondingO,N-diacetyl derivatives. The O,N- diacetyl derivatives can in turn bereadily separated on the basis of their widely different solubilitycharacteristics in water. in hy-drolyzing off one of the O-acetyl groupsfrom the completely acetylated l-thienyl-Z-amino-l,3-propanediolcompound, boiling water alone is employed. It is not necessary to addeither an acidic or a basic agent or a catalyst.

.When a nitro group is desired on the 5-position of the thienyl radicalin the final product (assuming R2 is hydrogen at this point) it ispreferred to add a nitration step to the general process graphicallyshown above. Nitration of the completely acetylatedl-(2-thienyl)-2-amino-1,3- propanediol compound of Step 6 is preferablycarried out using fuming nitric acid and acetic anhydride. In allinstances the temperature of the reaction mixture should be kept between-20 and C. A preferred temperature is about 5 C.

The next step of my general process, Step 7, is to hydrolyze off all theacyl groups in the completely acylatedI-(Z-thienyl)-2-amino-1,3-propanediol. Acidic or alkaline conditions canbe used to accomplish this hydrolysis. Dilute acid is preferred. Itbrings about the complete hydrolysis in a short time. .The acid isneutralized with caustic prior to extraction.

In carrying out Step 8 the amino diol is treated with an acylating agentunder mild acylating conditions. In order to eliminate the possibilityof polyacylation, I prefer to use (1) an acyl anhydride or halide undersubstantially anhydrous conditions at low temperature, (2) an acylanhydride or halide in a mildly alkaline aqueous reaction medium or (3)an ester type acylating agent or halide under substantially anhydrousconditions.

When an acyl anhydride or halide is used under substantially anhydrousconditions for the acylation in Step 8, the

temperature should be kept below about 10 C. A temperature of about 0 C.is preferred. It is particularly preferred to carry out the reaction inan inert organic solvent, such as for instance, esters of lower fattyacids, for example, ethyl acetate; lower aliphatic ketones, for example,acetone or methyi ethyl ketone; cyclic ether, for example, dioxane;hydrocarbons, for example, benzene; and, halogenated aliphatichydrocarbons, for example, ethylene dichloride and chloroform.

The acylation can also be effected using an acyl halide or anhydride asthe acylating agent in an aqueous medium. The reaction is preferablycarried out at a temperature below the boiling point of the mixture. ThepH of the aqueous medium is maintained at a value greater than Any of awide variety of materials may be used to maintain the mixture at theproper pH. There may be used, for instance, alkali metal acetates,bicarbonates, carbonates and hydroxides; alkaline earth hydroxides; andtertiary amines, for example, pyridine, triethylamine and the like.

The aqueous reaction medium may contain a watermiscible orwater-immiscible organic solvent. Usually water alone is satisfactory.If the amino diol is waterinsoluble, it is advantageous to increase itssolubility by adding a water-miscible organic solvent such as, forinstance, methanol, ethanol or acetone.

In those instances where the acylating agent is quite reactive, it ispreferred to use a two-phase system in order to reduce the exposure ofthe final product to unreacted acylating agent. This is effected byusing as the reaction medium a mixture of water and a water immiscibleorill ganic solvent such as, for instance, ethyl acetate, chloroform,ether, carbon tetrachloride, and the like.

When an ester is used as the acylating agent in Step 8 the optimumreaction conditions are dependent upon (1) the reactivity of the esteritself and (2) the reactivity of any potentially active substituents ofthe ester. For esters of a given acid the lower alipahtic alkyl estersare more reactive than higher aliphatic alkyl esters. They arepreferred. Of the lower alkyl types, the methyl esters are preferred.

Using very reactive esters such as, for instance, methyldichloroacetate, and maintaining the temperature in the range of from 50to 100 C., the acylation reaction is substantially complete in periodsof from one-half to three hours.

Relatively inert esters, such as, for instance, methyl benzoate, do notreact with the amino diol obtained in Step 7 within a reasonable periodof time. A catalyst such as, for instance, an alkali alcoholate is addedto accelerate the acylation.

When methyl dibromoacetate is used at a temperature of about 100 C., itreacts with the amino diol of Step 7 to form cyclic amide-others. Thecyclic amide-ethers are undesirable products. To avoid the undesirableside reaction a lower reaction temperature, say, to 60 C. isrecommended. The use of an inert diluent such as, for instance, ethylalcohol is also helpful.

Of the several different procedures described above for carrying out themono N-acylation of the amino diol, one method or procedure may bepreferable for a given situation. Similarly, with a given procedure theoptimal conditions or reagents used may vary somewhat depending on theparticular reactants.

For instance, when the final product desired has at least onealpha-halogen on the acyl group the choice of a method of acylation isto some extent dependent upon the reactivity of the halogen atom(s).Thus, in the case of the mono-, diand tri-chloro-acetyl radicals, thehalogens are relatively inert and the thienyl acylarnido diol compoundsof the invention can be prepared by any of the methods described above.

However, with more reactive halogen atoms, such as, for instance,alpha-bromo and alpha-iodo acyl radicals, the preferred method ofpreparing the corresponding acylamido diol compounds is to react theamino diol with the haloacyl halide in a substantially anhydrous, inertorganic solvent such as, for instance, ethyl acetate.

In some instances, particularly if R2 is halogen and R1 is hydrogen, itis advantageous to eliminate Step 8 by employing a di'haloacetyl halideas the acylating agent in Step 3 of my process.

Step 8 may also be eliminated by a selective hydrolysis of the O-acylgroups present in the polyacylated amino diol compound obtained fromStep 6. The hydrolysis is effected by treating the polyacylated aminodiol at a temperature of from -15 to C. with a strongly alkalinematerial using as the reaction medium a mixture consisting of water anda water-miscible organic solvent.

Any of a wide variety of alkaline materials may be used in treating thepolyacylated amino diol. There may be used, for instance, alkali metalhydroxides, alkaline earth metal hydroxides and alkali metal carbonates.

Water-miscible organic solvents suitable for use in the selectivehydrolysis of the O-acyl groups include lower aliphatic alcohols suchas, for example, methanol, ethanol and isopropanol; lower aliphaticketones such as, for example, acetone and methyl ethyl ketone; andcyclic ethers such as, for example, dioxane.

The preferred method of eifecting the selective hydrolysis is tomaintain the temperature at about 0 C. and to use only a slight excessof alkali over the amount necessary to bring about hydrolysis of theO-acyl group or groups. The solvent of choice for carrying out thereaction in this fashion is about a 50% aqueous solution of a loweraliphatic alcohol such as, for instance, methanol, or a lower aliphaticketone such as, for instance,

acetone.

Although the individual A or B stereoisomeric forms of thel-(2-thienyl-2-amido-1,3-propanediol compound can be resolved into theiroptical isomers earlier in the process, I prefer to carry out theresolution following the completion of Step 7. This resolution may becarried out by forming an acid addition salt of the racernic amine ofeither form A or B with an optically active acid such as, for instance,(d)-camphor sulfonic acid, (l)-carnphor sulfonic acid, (d)-tartaric,(l)-tartaric, (d)-rnandelic and (l)-mandelic; separating the twodiastereoisomeric products by recrystallization from a solvent such as,for instance, a lower aliphatic alcohol or mixtures of the same withwater or other organic solvents; and then regenerating the individualoptically active isomers from the separated diastereoisomeric additionsalts by treating each one separately with caustic.

When carrying out the resolution, as set forth above, it is desirablebut not essential to choose the form of the optically active acid sothat the diastereoisomer of which the desired optical isomer is a partwill separate from the crystallization solution first.

The compounds of the present invention are useful in the preparation ofother organic compounds and find particular use as bacteriostaticagents. Some of the products of this invention have given evidence ofgreat value as bactericides.

The invention is further illustrated by the following examples:

Example 1 Preparation of (d!) -B-l--nitro-2-thienyl)-2-dichloroacetamido-1,3-propanediol.

on ITIHC 0 011011 OzN dH-cr1 on.o11

(CU) -B form N (2 thenoylmethyl)hexamethylenetetraminium bromide,prepared from 2-acetylthiophene by bromination followed by addition ofthe resulting bromo compound in chloroform to hexamethylenetetrarnine,is hydrolyzed to (2-thenoylmethyl)arnine hydrochloride as follows:

A mixture consisting of 984 g. of N-(2-thenoylmethyl)-hexamethylenetetraminiurn bromide, 1,190 ml. of concen tratedhydrochloric acid and 2 liters of 95 per cent ethanol is heated at atemperature of about 50 C. for a period of about one and a half hours.and the ammonium halides, which separated during the reaction period,are filtered off. The filtrate is concentrated by distillation underreduced pressure. The crystalline solid, which separates from theconcentrated filtrate,

The mixture is then cooled I is collected, washed with ethanol and withether, and If? finally dried in vacuo.

The product obtained in the above manner is (2--thenoylmethyl)aminehydrochloride. It can be represented by the following formula:

o S eneral-n01 perature of mixture is maintained below about C.

After the temperature of the reaction mixture is allowed to rise toabout C. the mixture is acidified with hydrochloric acid. The solidwhich separates is collected, washed, and dried in vacuo.

The dried product consists ofN-(Z-thenoylmethyD- acetamide. It ispurified by recrystallization from per cent aqueous ethanol. M. P.l2ll22 C. The formula of the compound is:

Analysis calculated for Cal-lgNOzS: C, 52.44; H, 4.95; N, 7.65. Found:C, 52.48; H, 5.07; N, 7.81.

2.75 g. of sodium bicarbonate is added to a mixture composed of 550 g.of N-(Z-thenoylmethyl)acetamide, 1100 ml. of water, and 452 ml. of 37per cent aqueous formaldehyde. The temperature of the reaction mixtureis maintained at about C. and the reaction is continued until a clearsolution results. This usually requires about minutes. The reactionmixture is then stirred for a period of about three hours at roomtemperature. Finally it is cooled. An insoluble product is collected,washed with water, dried, and recrystallized from ethyl acetate. Thepurified product melts at 108- li0 C. it is (all) N [2hydroxy-l-(2-thenoyl)ethyl] acetamide, and has the formula I 0 Nnooom(Lilli-$112011 I s Analysis calculated for C9H11N03SZ C, 50.69, H, 5.20;5, 15.03. Found: C, 50.70; H, 5.23; S, 14.70.

A solution of 3.8 g. of per cent sodium borohydride in 75 ml. ofmethanol is added over a period of about twenty minutes to a methanolicsolution of 75 g. of (d1)- N- [2-hydroxyl- Z-thenoyl ethyl] acetamidemaintained at a temperature of from 20 to 25 C. throughout the entireaddition. The reaction mixture is then stirred for a period of aboutfifteen minutes. The methanol is distilled from the reaction mixtureunder reduced pressure. The residue is mixed with 200 ml. of water, andwarmed on a steam bath for a period of about thirty minutes. The aqueoussolution is saturated with sodium chloride, and extracted with ethylacetate. The extract is dried and the ethyl acetate is evaporated toobtain an isomeric mixture consisting ofl-(2-thienyl)-2-acetamido-l,3-propenediol (M. P. lllll C.) having theformula In order to separate the diastereoisomeric pairs heroinabovereferred to as the A and B forms, 71 g. of a mixture consisting of(dI)-A- and (dl)-B-1-(2-thienyl)-2- acetamido-l,3-propanediols, 142 ml.of acetic anhydride, and 142 ml. of pyridine is heated in a steam bathfor a period of about one-half hour. The reacted mixture is evaporatedunder reduced pressure. The residue is a mixture consisting of thetriaeetyl derivatives of both forms; that is, A and B, ofl-(Z-thienyl)-2-amino-l,3 propanediol. By successive crystallization ofthe residue from absolute ethanol pure (dl)-A-1-(2-thienyl)-2-acetamido-1,3-propanediol diacetate (M. P. ll3ll4 C.) is obtained.

A variation of this procedure, which I find more efficient, is tohydrolyze the mixed isomeric triacetyl derivatives to the N,O-diacetylderivatives. A mixture consisting of the1-(2-thienyl)-2-acetamido-1,3-propanediol diacetate (49.2 g.) isdissolved in 900 ml. of boiling water. After the volume of the solutionis reduced to about 325 ml. by boiling at atmospheric pressure in anopen vessel, the solution is chilled in an ice bath. The resultinginsoluble product is collected and purified by recrystallization fromwater; M. P. l42-l4-3 C. The product obtained in this manner is theN,O-diacetyl derivative (al- B-I-(Z-thienyl) -2-amino-1,3-propanediol.

Analysis calculated for Girl-N045: C, 51.34; H, 5.88; N, 5.44. Found: C,51.25; H, 5.89; N, 5.40.

The mother liquors from'the separation of the B diacetyl compounddescribed above are evaporated to dryness under reduced pressure. Thegummy residue is acetylated with a mixture consisting of aceticanhydride and pyridine. The product thus obtained is purified byrecrystallization from absolute ethanol; M. P. 113-114 C. The product II 0000113 NHCOCHa s 41H JH-OHzOCOCHa (dZ)-B form Analysis calculated forC13H1'2NO5S: C, 52.16; H, 5.73; N, 4.68. Found: C, 52.08; H, 5.80; N,4.67.

A mixture consisting of l g. of the N,O-diacetyl derivative of(dl)-B-l-(2-thienyl)-2-amino-1,3-propanediol, 50 ml. of 0.1N sodiumhydroxide and 50 ml. of acetone is stirred over a period of about onehour While the temperature is maintained at about C. The reactionmixture is neutralized with hydrochloric acid and the acetone re moved.by distillation under reduced pressure. The solution is extracted withethyl acetate and the extracts are dried and concentrated to drynessunder reduced pressure. The residue which is(dl)-B-1-(2-thienyl)-2-acetamido- 1,3-propanediol, is purified byrecrystallization from ethyl acetate; M. P. 142.5-143.5 C. The formulafor this product is OH iruzrooom S lH-OHCH2OH (611) -B form Analysiscalculated for C9H13NO3S: C, 50.21; H, 6.09; Y

N, 6.51. Found: C, 50.36; H, 6.29; N, 6.51.

In like manner, (dl)-A-l-(2-thienyl)-2-acetamido-1,3- propanediol isprepared from the triacetyl derivative of (dl)-A-1-(2-thienyl) a 2amino-1,3-propanediol. This A diastereoisomeric form of1-(2-thienyl)-2-acetarnido-l,3- propanediol has a melting point of144.5145.0 C. Mixtures of this product with the B-N,O-diacetylderivative and also with(dl)-B-1-(2-thienyl)-2-acetamido-1,3-propanediol give depressed meltingpoints.

4.3 g. of fuming nitric acid (density=1.5) is added over a period ofabout 33 minutes to a previously cooled, stirred mixture consisting of13.0 g. of (dl)-A-1-(2-thienyl)-2- acetamido-1,3-propanediol diacetate.During the addition the temperature of the reaction mixture ismaintained between 0 and C.

After a period of about one half-hour the reaction mixture is pouredonto 100 g. of ice and neutralized with sodium bicarbonate. Theresulting mixture is extracted with several portions of ethyl acetate.The extracts are dried with anhydrous magnesium sulfate. The ethylacetate is distilled from the combined extracts under reduced pressure.The residual (dl)-A-1-(5-nitro-2-thienyl)-2- acetamido-1,3-propanedioldiacetate is purified by recrystallization from Water. The purifiedproduct melts at 139-141 C. and has the formula (all) A form Analysiscalculated for C1sH16N2O'zS: C, 45.34; H, 4.68; N, 8.14; S, 9.31.FoundrC, 45.30; H, 4.66; N, 8:06; S, 9.25. p

The corresponding (dl)-B form is prepared in an identical manner. Whenpurified by recrystallization from water this compound had a M. P. of119120-C. Analysis calculated for C13H16N2O7S: C, 45.34; H, 4.68; N,8.14; S, 9.31. Found: C, 45.45; H, 4.77; N, 7.94.

Without purification, the residue consisting of (all) -B-1-(5-nitro-2-thienyl)-2-acetamido-1,3-propanediol diacetate obtained fromthe nitration of 24.0 g. of (dl)-B-1-(2-thienyl)-2*acetamido-1,3-propanediol diacetate is heated on a steam bathin the presence of 320 ml. of 1.5N hydrochloric acid for a period offrom two to three hours. The reaction mixture is decolorized and theaqueous solution is concentrated under reduced pressure. The resultingconcentrate is cooled and made alkaline to pH 9-10 with 6N sodiumhydroxide solution. The product which separates is collected, Washed anddried. Recrystallization from Water yields the desired(dl)-B'-1-(5-nitro-2- thienyl)-2-amino-l,3-propanediol (M. P. l23127 C.partially purified) of formula,

I on uni oiN \s/ dn-dn-o mon (dl)-B form By substituting(dl)-A-1-(5-nitro 2 thienyl)-2-acetamido1,3-propanediol diacetate forthe (dl) -B-diastereoisomer used in the above procedure one obtains(dl)-A-1- (S-nitro-Z-thienyl)-2-amino-1,3-propanediol (M. P. C. crude).

A mixture consisting of 4.5 g. of (dl)-B-1-(5-nitro-2-thienyl)-2-arnino-1,3-propanediol and 25 ml. of methyl dichloroacetateis heated at a temperature of 100 C. for a period of one and a halfhours. The residue is washed with petroleum ether and extracted withboiling ethylene dichloride. The solvent is evaporated under reducedpressure to obtain a crystalline product consisting of(dl)-B-1-(5-nitro-2-thienyl)-2 dichloroacetamido 1,3- propanediol. Thisproduct can be purified by recrystallization from water; M. P.131.5132.0 C.

The formula of this compound is I I OH NHCOCHCh oiN- 11-onoienon ((1043form Analysis calculated for C9H1oCl2N205S: C, 32.84; H, 3.06; N, 8.51;S, 9.74. Found: C, 32.67; H, 3.39; N,

The new product,(d1)-B-1-(5-nitro-2-thienyl)-2-dichloroacetamido-1,3-propanediol, isstrongly active bacteriostatically. It has also given evidence of greatvalue as a bactericide, particularly against organisms, such as, forexample, Shigella paradysenteriae, Escherichia coll, Bacillus subtz'lisand Salomonella typhosa.

By employing the corresponding (dl)-A-base in the above procedure oneobtains (dl)-A-l-(5-nitro-2-thienyl) 2 dichloroacetamido 1,3propanediol; M. P. 168.5169.5 C.

Analysis calculated for CsHmClzNzOsS: C, 32.84; H, 3.06; N, 8.51. Found:C, 33.02; H, 3.32; N, 8.39.

The corresponding A diastereoisomeric pair prior to resolution exhibitsa A max at 330 m and a s max of 9,260 (aqueous solution) on ultra violetabsorption spectrum analysis.

The optically active forms (d and l) of B-1-(5-nitro-Z-thienyl)-2-dichloroacetamido-1,3-propanediol can be prepared by thefollowing procedure:

10.9 g. of (dl)-B-1-(5-nitro-2-thienyl)-2-amino-1,3- propanediol isdissolved in a solution of 11.6 g. of dcamphor sulfonic acid in 410 ml.of isopropanol by warming themixture briefly on a steam bath. Theresulting solution is allowed to stand. The first isomer to separatefrom the solution is the (d)-camphor sulfonic acid salt of propanediol.On purification by recrystallization from isopropanol this salt has a M.P. 185186 C. and [a] -|5.72 (aqueous solution at a concentration of 40mg./ml.).

Analysis calculated for C17H2sN2OaS: C, 45.32; H, 5.82; N, 6.22. Found:C, 45.28; H, 6.05; N, 6.32.

After removal of the (d)-acid salt of the (l)-basc, the corresponding(d)-acid salt of the isomeric (d)-base is recovered from the combinedfiltrates. On purification by recrystallization from isopropanol thesalt has a M. P.

172.51735" C. and [a] +20.7 (aqueous solution at a concentration of 40mg./ml.).

Analysis calculated for CnHzsNzOsS: C, 45.32; H, 5.82; N, 6.22. Found:C, 45.61; H, 6.15; N, 6.35.

The (d)-camphor sulfonic acid salt of (l)B-1-(5-nitro-2-thienyl)-2-amino-1,3-propanediol obtained above is dissolved inwater and the solution made alkaline to pH 9-10 with ammonium hydroxide.The solution is then extracted with ethyl acetate. The extracts aredried and evaporated under reduced pressure giving (l)-B-1-(5-nitro-2-thienyl)-2-amino-1,3-propanediol. This compound may berepresented by the formula (Z)-B form By a similar procedure one mayobtain (d)-B-1-(5- nitro-Z-thienyl)-2-amino-1,3-propanediol from the(d)- camphor sulfonic acid salt of (d) -B-1-5-nitro-2-thienyl)-2-amino-1,3-propanediol.

(l)-B-l-(5nitro 2 thienyl) 2 dichloroacetamido- 1,3-propanediol isprepared by reacting the (l)-B-base with an excess of methyldichloroacetate as described above for the case of the (dl)-B-isomer. Onpurification by recrystallization from ethylene dichloride the pure (l)-B-1-(5-nitro-2-thienyl) 2 dichloroacetamido 1,3- propanediol has a M.P. 107.5107.7 C. and [a] -153, and exhibits a A max with a molecularextinction coefficient (e max) of 9,270.

Analysis calculated for C9H1oC12N2O5S: C, 32.84; H, 3.06; N, 8.51.Found: C, 33.11; H, 3.17; N, 8.61.

(d)-B-1-(5-nitro-2 thienyl) 2 dichloroacetamido- 1,3-propanediol isprepared by a similar procedure. On purification by recrystallizationfrom ethylenedichloride the pure (d) -B-1-(S-nitro-2-thienyl)-2-dichloroacetamido-1,3-propanedio1 has M. P. 106.5-107.5 C. and [a]+150.

Analysis calculated for C9H1oCl2N2O5S: C, 32.84; H, 3.06; N, 8.51.Found: C, 32.85; H, 3.26; N, 8.44.

Example 2 Preparation of (dl) B1-(5-bromo-2-thienyl)-2-dichloroacetamido-1,3-propanediol (d1) -B form5-bromo-2-acetylthiophene is prepared by the aceylation of2-bromothiophene using acetic anhydride and 85% orthophosphoric acidaccording to the method of Hartough and Conley (I. Am. Chem. Soc. 6 9,3096 (1947)).

(l) -B-1- 5-nitro-2-thienyl) -2-amino- 1, 3 1

A solution of 820 g. of 5-bromo-2-acetylthiophene in one liter ofglacial acetic acid is irradiated with ultraviolet light. To thissolution there is added 640 g. of bromine with stirring over a periodabout two hours. The temperature of the reaction mixture is maintainedby means of an ice bath at a temperature of from about 15 to 20 C. Thesolution is stirred for -a period of two hours after the bromineaddition. During this two hour period a stream of dry nitrogen is passedthru the solution to sweep out hydrogen bromide.

The reaction mixture is then poured into about 2 liters of ice water. Asolid product (M. P. 93-935 when purified by recrystallization fromcarbon tetrachloride) is collected on a filter, washed with water, anddried. The product is dissolved in about 2 liters of chloroform.

The chloroform solution obtained as above described is added to amixture consisting of 5 g. of hexamethylenetetramine and 2 liters ofchloroform. The temperature of the resulting mixture rises rapidly. Thereaction is moderated using an ice bath. After the initial exothermicreaction has subsided, the stirred mixture is maintained at atemperature of about 60 C. for a period of four hours. The mixture iscooled and the solid, which has separated, is collected, washedsuccessively with absolute ethanol and ether, and dried. The productconsisting of N-(5-bromo-2-thenoylmethyl)hexamethylenetetraminiumbromide (M. P. 169.5 C. decomposed) has the formula C H2N Analysiscalculated for C12H1sBr2N4OS: Br, 37.68. Found: Br, 38.05.

A mixture consisting of 1210 g. of N-(5-bromo-2-thenoylmethyl)hexamethylenetetraminium bromide, 1.2 liters ofconcentrated hydrochloric acid, and 2.5 liters of 95 per cent ethanol isheatedat a temperature of 50 C. for a period of about one and one-halfhours. The mixture is then cooled in an ice bath. The solid materialconsisting of ammonium halides plus some of the desired [(5 bromo 2thenoyl) methylJamine hydrochloride, which has separated, is collectedon a filter and after drying amounts to about 1000 g. This mixture isstirred for a period of 15 minutes at a temperature of 10 C. with 1800ml. of water. The undissolved solid, consisting mainly ofN-[(S-bromo-Z-thenoyl)methyl]amine hydrochloride, is collected on afilter and Washed first with absolute ethanol, then with ether, andfinally airdried.

Upon concentrating the filtrate by distillation under reduced pressure,an additional amount of [(5-bromo-2- thcnoyl)methyl] amine hydrochlorideseparates. The precipitated material is collected, washed with ethanoland ether, and dried. The total product consisting of [(5-bromo-2-thenoyl)methyll amine hydrochloride is used without furtherpurification. It has the following formula Analysis calculated forCsi-iqBrClNOS: N, 5.46. Found: N, 5.45.

A mixture consisting of 1,280 g. of [(5-brorno-2- thenoyl)methyl] aminehydrochloride and 3 liters of water is cooled to a temperature of about0 C. 1,020 grams of acetic anhydride is added thereto. To the resultingmixture there is added a solution of 1,358 g. of sodium acetatetrihydrate in 2.5 liters of water over a period of about ten minutes.During this addition the reaction mixture is kept at a temperature below10 C. After the temperature of the mixture has risen to about 20 C.,

the mixture is acidified with concentrated hydrochloric acid. A solidproduct which separates from the solution is collected, Washed anddried.

An additional quantity of the solid product is obtained by saturatingthe combined filtrates and washings with sodium chloride and extractingwith five 700 ml. portions of ethyl acetate. The combined ethyl acetateextracts are dried over sodium sulfate and concentrated under reducedpressure to a volume of about 350 ml. One liter of petroleum ether isadded to the warm concentrate. Upon cooling the mixture in an ice bath,crystals are deposited/ They are collected and dried in vacuo. Thecrystalline product so obtained is N-(S- bromo-Z-thenoylmethyl)acetamideand has the formula This compound may be purified by recrystallizationfrom water or aqueous ethanol to give a product with M. P. 143-144" C.

Analysis calculated for CsHsBrNOzS! C, 36.65; H, 3.07; N, 5.34. Found:C, 36.58; H, 3.06; N. 5.22.

To a mixture consisting of 786 g. of (dl)-N-[(-bromo-2-thenoyl)methyllacetamide, 2,240 ml. of 95% ethanol and 388 ml. of36-38% aqueous formaldehyde there is added 30.2 g. of sodiumbicarbonate. The reaction mixture is stirred for a period of about onehour while at a temperature of about 35 C. The stirred mixture cools toroom temperature in a period of about 3 hours. The insoluble materialwhich separates is collected and washed with a small amount of coldwater. It is dried overnight in a vacuum oven at a temperature of fromabout 60 to 70 C. The product obtained is mainly(dl)-N-[2-hydroxy-1-(5-bromo-2-thenoyl)ethyl] acetamide, which has theformula 3 I r) nncoom Br S o-bn-onton This product when purified byrecrystallization from ethyl acetate has M. P. 140141 C.

Analysis calculated for C9H10BINO3S: Found: N, 4.59.

A solution of 3.8 g. of 95% sodium borohydride in 75 ml. of methanol isadded over a period of about 25 minutes to a mixture consisting of 103g. of (dl)-N-[2 hydroxy-l-(5-bromo-2-thenoyl)ethyl]acetamide and 350 ml.of methanol. The temperature of the reaction mixture is maintained inthe range of from to C. throughout the addition. The reaction mixture isstirred for an additional period of about fifteen minutes. The methanolis then removed from the mixture by distillation under reduced pressure.

The residue is mixed with 300 ml. of Water and formula on NH0 0 CH3 BrCH-( JHCH2OH The (a'l)-A form and the (dl)-B form may be separated ifdesired by fractional crystallization from ethyl acetate or dioxane. Analternative method of separating these two forms is to acetylate themixture of these forms prepared as above described. Acetylation iscarried out by heating the mixture on a steam bath for a period ofone-half hour with an excess of acetic anhydride and a correspondingvolume of pyridine. In this way a mixture of the (dl)-A and (dl)-B formsof the corresponding triacetate is formed which may be represented bythe following formula OOOCHa NHCOCHa I l on CH-CH2OCOCH3 formula (|)HlTTHa Br S CH-CHOH2OH (dl) -'B form A mixture consisting of 6.0 g. of(dl)-B-1-(5-bromo-2- thienyl)-2-amino-1,3propanediol and 25 ml. ofmethyl dichloroacetate is heated on a steam bath for a period of about1.5 hours. The reaction mixture is cooled and extracted with ml. ofpetroleum ether. The residue is Washed twice with 50 ml. of petroleumether and then extracted'with two 100 ml. portions of boiling ethylacetate. The combined hot ethyl acetate extracts are treated withdecolorizing charcoal. The ethyl acetate is then removed by distillationunder reduced pressure.

The residual (dl)-B-1-(5-bromo-2-thienyl)-2-dichloroacetamido-1,3-propanediol is purifiedby recrystallization from aqueous ethanol. The formula of this productis I on 1;:110001101. Br S -oncn cnion (dl)-B form Example 3 Preparationof (dl)-B-1-(2-thienyl)-2-dichloroacetamido-1,3-propanediol,

l on lTIHC 0 01101,

cn-on-onion S/ (db-B form at from 0 to 5 C. The stirred mixture isallowed to .reach room temperature. It is then filtered.

The filtrate is washed successively With 300 ml. portions of water, 1.2N hydrochloric acid, water and 10% sodium bicarbonate. It is dried oversodium sulfate, and concentrated by distillation under reduced pressure.The residue is recrystallized from 1:1 Skellysolve B- ethylenedichloride to improve its purity and consists of pyridine.

, '15 N-(Z-thenoylmethyl)dichloroacetamide. It has the following formulav When highly pure, the above compound has a M. P. of 136.5137.5 C.Analysis calculated for CaHqOzNsClz: C, 38.11; H, 2.80; Cl 28.13; S,12.72. Found: C, 38.11; H, 3.05; Cl 27.90; S, 12.73.

A mixture consisting of 60 g. of N-(2-thenoylmethyl)- dichloroacetamide,480ml. of methanol, 40 g. of 3638% aqueous formaldehyde and 1.9 g. ofsodium bicarbonate is prepared, stirred and heated to a temperature ofabout 35 C. for a period of about one hour. Stirring of the mixture iscontinued while the mixture cools to room temperature. The coolingrequires about one and onehalf hours. The mixture is chilled and pouredinto 800 g. of ice and water. The precipitate which has separated iscollected, washed with cold Water, and dried. The product is(dl)-N-[2-hydroxy-1-(2-thenoy1)ethyl]dichloroacetamide and has theformula When highly pure, the compound has a M. P. of 118.5- 119.5 C.Analysis calculated for C9H903NSC12Z C, 38.31; H, 3.21; Cl, 25.13; S,11.36. Found: C, 38.85; H, 3.63; Cl, 25.18; S, 10.97.

A solution of 1.9 g. of 95% sodium borohydride in 40 ml. of methanol isadded over a period of about 20 minutes to a solution of 49.6 g. of(dl)-N-[2hydroxyl-1- (2-thenoyl)ethylldichloroacetamide in 200 ml. ofmethanol. The methanol solution of (dl)-N-[2-hydroxyl-1-(Z-thenoyl)ethyl]dichloroacetamide is maintained at a temperature ofabout 2025 C. throughout the sodium borohydride addition. The reactionmixture is stirred for a period of minutes following the completeaddition of the sodium borohydride solution. The methanol is removed bydistillation under reduced pressure.

The residue is mixed with 40ml. of water and warmed on the steam bathfor a period of about one-half hour. The aqueous solution is thensaturated with sodium chloride and extracted with ethyl acetate. Theethyl acetate extracts are dried with sodium sulfate, and concentratedby distillation under reduced pressure. The residue is triturated with25 ml. of ether. The solid product is then collected and washed withether. The product, (dl)-AB-1-(2-thienyl)-2-dichloroacetamido-1,3-propanediol, is a mixture of spaceisomers which may be represented by the following formula:

Separation of the (al) -A and (dl)-B forms of this product may beeffected at this point by fractional crystallization from ethyl acetateor dioxane.

In an alternate method for the preparation of the pure (dl)-A or (dl)-Bforms of the product, g. of the (d1)- AB- 1- Z-thienyl)-2-dichloroacetamido- 1 ,3-propanediol is mixed with 40 ml. of aceticanhydride and 40 ml. of The resulting solution is heated on the steambath for a period of about one-half hour. The excess anhydride andpyridine are removed by distillation under reduced pressure.

The residue consists primarily of a mixture of the isomeric1-(2-thienyl) -2-dichloroacetamido-1,3 -propanediol diacetates and maybe represented by the formula,

By fractional crystallization of this crude product from absoluteethanol, one may separate the (dl)-A and the (dl)-B forms of the abovecompound.

When highly pure, the (dZ)-A and (dl)-B forms melt respectively at93.5-94.5 C. and 122123 C. Analysis calculated for CisHrsOsNSClz: C,42.40; H, 4.11; S, 8.71. Found (dl)-A: C, 42.47; H, 4.23; S, 8.49. Found(dl)-B: C, 42.33; H, 4.52; S, 8.45.

1 g. of (dl)-B-1-(2-thienyl)-2-dichloroacetamido1,3- propanedioldiacetate is stirred with 50 ml. of 0.2 N aqueous sodium hydroxide and50 ml. of acetone at a temperature of from about 0 to 5 C. for a periodof about one hour. The mixture is then carefully neutralized by theaddition of aqueous hydrochloric acid. The acetone is evaporated underreduced pressure.

The resulting aqueous solution is extracted five times with 25 ml.portions of ethyl acetate. The combined ethyl acetate extracts are driedwith magnesium sulfate, and concentrated to dryness by distillationunder reduced pressure. The residue is recrystallized from ethylacetate.

in this way the pure(dl)-B-1-(2-thienyl)-2-dichloroacetamido-1,3-propanediol is obtained.

By carrying out a similar hydrolysis starting with (d2)-A-1-(2-thienyl)-2-dichloroacetamido-1,3 propanediol diacetate, the pure(dl)-A-1-(2-thienyl)-2-dichloroacetarnido-1,3-propanediol can beprepared. When highly pure, the compound has a M. P. of 151.5153 C.Analysis calculated for CsHnOsNSClz: C, 38.04; H, 3.90; S, 11.28. Found:C, 37.77; H, 4.12; S, 11.28.

Example 4 Preparation of(dl)-B-1-(5-methyl-2-thienyl)-2-dichloroacetamido-1,3-propanediol,

on unooonou CH3 s cnouomon (db-B form To a suspension of 623 g. ofanhydrous aluminum chloride in 2670 ml. of carbon tetrachloride there isadded 942 g. of bromoacetyl bromide over a period of about one-halfhour. The suspension is stirred and maintained at a temperature of about0 C. throughout the addition. 392 g. of Z-methylthiOphene is then addedto the resulting mixture over a period of about four hours. During thisaddition the temperature of the reaction mixture is kept below 5 C.After the addition of Z-methylthiophene is completed, the reactionmixture is stirred for an additional hour.

The reaction mixture is hydrolyzed by pouring into a stirred mixtureconsisting of ice and hydrochloric acid. The carbon tetrachloride layeris separated, washed with aqueous sodium carbonate solution, and dried.The carbon tetrachloride solution of 5-methyl-2-bromoacetylthiophene isused directly in the next reaction.

A mixture consisting of 585 g. of hexamethylenetetramine and 1.5 litersof chloroform is added to a carbon tetrachloride solution of5-methyl-2-bromoacetylthiophene. The temperature of the resultingmixture rises rapidly. The reaction is moderated by external cooling.After the initial exothermic reaction has subsided, the temperature ofthe reaction mixture is maintained at a temperature of about 50 C. for aperiod of about four hours. v p

The reaction mixture is cooled and the solid product, which hasseparated, is collected. The product is washed with 400 ml. of ether anddried under reduced pressure. The principal ingredient of the residuehaving the formula shown below isN-(5-methyl-2-thenoylmethyl)hexamethylenetetraminium bromide.

A mixture consisting of 1020 g. of N-(S-methyl-Z-thenoylmethyl)hexamethylenetetraminium bromide, 1200 ml. of concentratedhydrochloric acid, and 2 liters of 95% ethanol is heated at atemperature of about 50 C. for a period of about one and one-half hours.The mixture is then cooled in an ice bath.

The solid material consisting of ammonium halides and some of thedesired [(5-methyl-2-thenoyl)methyl]amine hydrochloride, which hasseparated, is collected on a filter. The solid material is dried andweighed approximately 450 g. It is stirred for a period of 15 minutes ata temperature of 10 C. with 1600 ml. of water. The undissolved solidconsisting mainly of [(5-methyl-2-thenoyl)- methyllamine hydrochlorideis collected on a filter, washed with absolute ethanol, then with etherand finally air-dried.

Upon concentrating the filtrate by distillation under reduced pressure,an additional amount of [(5-methy1-2- thenoyl)methyl]'aminehydrochloride separates. It is collected, washed successively withabsolute ethanol and ether and then dried. The total product consistingof 5 -methyl-2-thenoyl) methyl] amine hydrochloride is used withoutfurther purification. It has a M. P. of 215- 218 C. with decomposition.[(S-methyl-Z-thenoyl) methyHamine hydrochloride may be represented bythe formula I CH -CHBNH2-HCI To a mixture consisting of 19.2 g. of[(5-methyl-2- thenoyl)methyl]amine hydrochloride and 200 ml. of ethylenedichloride there is added in one portion 44.3 g. of dichloracetylchloride. The temperature of the stirred reaction mixture is heldbetween 05 C. during the addition of the dichloroacetyl chloride. Asolution prepared by dissolving 24 g. of sodium hydroxide pellets inenough Water to make 40 ml. of solution is added slow- 1y to thereaction mixture which is maintained at a temperature of from 0 to 5 C.The mixture is stirred for an hour after the addition is completed andfor another hour while the reaction mixture warms to room temperature.The mixture is then filtered.

The solid, which is collected upon filtration of the mixture, isextracted with 200 ml. of boiling ethylene dichloride and filtered. Thefiltrate is evaporated to dryness. A yellow product is obtained.

The original filtrate is separated from the heavy aqueous layer, washedtwice with water, then with sodi-,

um bicarbonate solution and dried over anhydrous magnesium sulfate. Theethylene dichloride solution is evaporated to dryness. An additionalquantity of yellow product is thus obtained.

The two portions of product are combined and recrys 0H S -CHrllTHAnalysis calculated for C9H9O2NSC12: C, 40.61; H,

3.41; S, 12.05. Found C, 40.51; H, 3.66; S, 12.02.

A mixture consisting of 66.5 g. of N-(5-methyl-2- thenoylmethyl)dichloroacetamide, 800 ml. of methanol, 37.7 g. of 36-38% aqueousformaldehyde and 1.9 g. of sodium bicarbonate is placed in a suitablereaction vessel. The mixture is stirred and maintainedat a temperatureof about 35 C. for a period of about two hours. The agitated mixture ispermitted to cool to room temperature. This requires about one andone-half hours. The reaction mixture is then chilled. A precipitate,which has formed, is collected and washed with cold water.

The filtrate is poured into 1500 g. of ice and water. The

18 solid which separates is collected by filtration, washed with coldwater and dried. It is recrystallized from ethyl acetate and combinedwith the main product collected above. The combined product isrecrystallized from 5 ethyl acetate. The product (dl)'-N-[2-hydroxy-l-('5- methyI-Z-thenOyDethyI]dichloroacetamide, is dried'preparatory 'to its use in the next step. It may be represented by thefollowing formula:

When pure, this compound has a M. P. of 153.5-

154.5 C. Analysis calculated for C1oH11O3NSCl2: C, 40.55; H, 3.74; Cl,23.94. Found C, 40.65; H, 3.82; CI,

A solution of 0.5 g. of 95% sodium bo'rohydride in 30 ml. of methanol isadded over a period "of about 20 minutes to a solution of 6.9 g. of (dl)-N-[2-hydroxyl-l-(5- 20 methyl-Z-thenoyDethYl]dichloroacetarnide in 40ml. of

methanol. The reaction mixture is maintained at a temperature of from 20to C. during the addition of the methanolic solution. The mixture isstirred for a period of about 15 minutes after the sodium borohydride 25solution has been added. The methanol is removed by distillation underreduced pressure.

The residue is mixed with 20 ml. of water and warmed on the steam bathfor a period of about one-half hour. The aqueous solution is thensaturated with sodium chloride and extracted several times with ethylacetate. The ethyl acetate extracts are dried with sodium sulfate. Theethyl acetate itself is removed by distillation under reduced pressure.The residue is triturated with 30 m1. of ether. A solid product whichseparates is collected and washed twice with 10 ml. portions of ether.The product,

(dl) -AB-1 (5-methyl-2-thienyl)-2-dich.loroacetamido-l,3- propanediol,may be represented by the formula,

I OH NHCOCHCJ:

The (dl)-A and (dl)-B forms of this product may be separated at thispoint in the synthesis by fractional crystallization from ethyl acetateor dioxane.

An alternate method for the preparation of the pure (dl)-A or (dl) Bform "is as follows: 20 g. of the (dl)- AB- 1- 5 -methyl-2thienyl)-2rdichloroacetamido- 1,3 propanediol is mixed with nil. ofacetic anhydride and 40 ml. of pyridine. The resulting solution isheated on the steam bath for a period of about one-half hour. The excessanhydride and pyridine are then removed by distillation under reducedpressure. The residue consists primarily of a mixture of the isomericcompounds, (dl) -AB- 1- S-methyl 2 1 thienyl) 2 dichloroacetoamido-1,3-propanediol diacetate. The following formula is representative:

hour. The reaction mixture is then carefully neutralized by the additionof aqueous hydrochloric acid. Acetone is removed by distillation underreduced pressure. The resulting aqueous solution is extracted five timeswith 25 ml. portions of ethyl acetate. The combined ethyl acetateextracts are dried with magnesium sulfate, and evaporated to drynessunder reduced pressure. The residue is further purified byrecrystallization from ethyl acetate. In this way pure(dl)-B-1-(5-methyl-2-thienyl)- 2-dichloroacetamido-1,3-propanediol isobtained.

By carrying out a similar hydrolysis starting with the (.dl)-A-1-(S-methyl-Z-thienyl) -2 dichloroacetamido 1,3- propanedioldiacetate, the pure (dl)-A-1-(5-methyl-2- thienyl)-2-dichloroacetarnido1,3 propanediol may be prepared. When highly pure, the (dl)-A form has aM. P. of 149150 C. Analysis calculated for C1oHi3O3NSCl2: C, 40.28; H,4.39; Cl, 23.78. Found: C,'40.12; H, 4.63; Cl, 23.80.

Example 5 Preparation of (dl)-B-1-(5-bromo-2-thienyl) 2dichloroacetamido-1,3-propanediol,

an uno 011012 Br- CH-CH-CHzOH (dl) -B form To a mixture consisting of17.3 g. of [(-bromo-2- thenoyl)rnethyl] amine hydrochloride and 250 ml.of ethylene dichloride there is added in one portion 29.5 g. ofdichloroacetyl chloride. The stirred reaction mixture is kept at atemperature of from 0 to 5 C. during the addition of the dichloroacetylchloride. A solution prepared by dissolving 16 g. of sodium hydroxidepellets in enough water to make 25 ml. of final solution is added slowlyto the reaction mixture, which is maintained at 0-5 C. The reactionmixture is stirred for a period of 15 minutes and then filtered.

The solid which is obtained is collected, extracted twice with 250 ml.of boiling ethylene dichloride and filtered. The filtrate is evaporatedto dryness. A light orange solid product is obtained.

The original reaction mixture filtrate is separated from the heavyaqueous layer,-washed twice with Water, then with sodium bicarbonate anddried over anhydrous sodium sulfate. The ethylene dichloride solution isevaporated to dryness. An additional quantity of orange solid product isobtained.

The two portions of product obtained in the above manner are combinedand recrystallized from a 1:1 mixture of Skellysolve B-ethylenedichloride. When highly pure, this compound,N-(5-bromo-2-thenoylmethyl)dichloroacetamide, has a melting point of151- 151.5 C.

V The compound may be represented by the formula,

I 3 $0 CHO]: Br s C-CHaNH Analysis calculated for CsHsOzSNBlClz: C,29.02; H, 1.82; S, 9.68. Found: C, 29.05; H, 2.10; S, 9.50.

A mixture consisting of 25.6 g. of N-(5-bromo-2-thenoylmethyl)dichloroacetamide, 120 ml. of methanol,

washed with a small amount'of Water and dried. The

filtrate is poured slowly onto 200 g. of ice and water. An additionalamount of product which separates is collected, dried and recrystallizedfrom benzene. The combined product is recrystallized from ethyl acetate.When highly pure, this compound, (dl)-N-[2-hydroxy-1-(5-bromo-2-thenoyl)ethyll dichloroacetamide, has a melting point of142.5-143 C. It has the formula 0 ITIHC 0 CH0]: Br s =CH-CH2OH Analysiscalculated for C9HsO3BrC12: C, 29.94; H, 2.23; S, 8.88. Found: C, 30.16;H, 2.40; S, 8.98.

A solution of 0.6 g. of sodium borohydride in 60 ml. of methanol isadded dropwise over a period of about 20 minutes to a solution of 17.2g. of (dl) -N-[2-hydroxy- 1-(5-bromo-2-thenoyl)ethyl] dichloroacetamidein ml. of methanol. The reactants are kept at a temperature of from 20to 25 C. by external cooling. The reaction mixture is stirred for aperiod of about 15 minutes.

After methanol is removed by distillation under reduced pressure, theresidue is mixed with 20 ml. of water and warmed on the steam bath for aperiod of about one- 1211f hour. The aqueous solution is saturated withsodium chloride and extracted with ethyl acetate. The ethyl acetateextracts are dried With sodium sulfate. Ethyl acetate is removed bydistillation under reduced pressure. The residue is triturated with 30ml. of ether, collected, washed with ether, and dried.

The P oduct so obtained is a mixture of space isomers of 1 (5bromo-2-thienyl)2-dichloroacetamido-1,3-propanediols and may berepresented by the formula,

An alternative method for the preparation of the pure (dB-A or (dl)-Bforms of the product comprises mixing 20.0 g. of the (dl)-AB-1-(2-thienyl)-2-dichloroacetamido- 1,3-propanediol with 40 ml. ofacetic anhydride in 40 ml. of pyridine and heating the resultingsolution on the steam bath for a period of about one-half hour. Theexcess acetylating agent and solvent are then removed by distillationunder reduced pressure. Theresidue consists primarily of a mixture ofthe isomeric diacetates of 1-(5- bromo 2thienyl)-2-dichloroacetamido-1,3-propanediol.

The following formula is representative of the product so obtained:

()COCHa lfnoocnon Br- S on oruomocoom is extracted five times with 25ml. portions of ethyl acetate. The combined ethyl acetate extracts aredried with magnesium sulfate, and then evaporated to dryness underreduced pressure. The residue consisting of (dl)-B-1-(5- bromo2-thienyl) -2-dichloroacetamido-1,3-propanediol is recrystallized fromethyl acetate to enhance its purity.

By carrying out a similarhydrolysis starting with the ,(dl) A l (5 bromoZ-thienyl)-2-dichloroacetamido- 1,3-pro'panediol diac'etate,,(dl)-A-1-(5-bromo-2 thienyl)- Z-diChIQrOacetamid w1-,3-P P ayb p p"arr-1am I 2i Ex'zzmplizo 4 Preparation of (al)-B-1-(3-methyl-5-nitro-2-thienyl)- 2-dichloroacetamido-1,3-propahedi0lCh is on Nuoo'oiroh OiN S. H-V H-CH2OH 942 g. of bromoacetyl bromide isadded to a :suspension of 623 g. of anhydrous aluminum chloride in 2670ml. of carbon tetrachloride and the resulting mixture cooled to atemperature of about C. for a period of about one-half hour. To themixture there is added 392 g. of 3-methylthiophene :over a period ofabout four hours. During the addition of the 3-methylthiophene thetemperature is maintained below C. The reaction mixture is stirred foran additional hour prior to hydrolysis. r

The reaction mixture is hydrolyzed by pouring it into a stirred mixtureof ice and hydrochloric acid. The carbon tetrachloride layer isseparated, washed with sodium carbonate solution, then with water, anddried using anhydrous sodium sulfate. The carbon tetrachloride isremoved by distillation under reduced pressure. A residue is left whichconsists mainly of 3'-methyl-'2 -t romacetylthiophene. Some4-mefl1yl-2-bromoacetylthiophene is also formed in the "reaction.

The crude 3-methyl-2-bromoacetylthiophene 'is dissolved in 1200 ml. ofchloroform, and the resulting chloroform solution is added in oneportion to a mixture consisting of 585 g. of hexamethyle'netetramine and1.5 liters of chloroform. The temperature of the resulting mixture risesrapidly and the reaction is moderated using an ice bath. After theinitial jexotihermic reaction has subsided, the reaction mixture ismaintained at a temperature of about 60 C. by external heating with asteam bath for a period of about four hours. The reaction mixture isthen cooled. I

A solid product, which has separated, is collected, stirred briefly with1 liter of absolute ethanol, filtered, collected, washed successivelywith 400 ml. of absolute ethanol and 400 m1. of ether, and dried. TheN-S-inethyl-2-thenoylmethyl)hexamethylenetetraminium bromide so obtainedhas the formula,

1,020. g. of acetic anhydride is added to a mixture consistin'g of 955g. of [(3-methyl-2-thenoyl)methyllamine hydrochloride and 2.5 liters ofwater previously cooled to a temperature of 0 C. To the resultingmixture there is added over a period of about 12 minutes a solution of1,358 g. of sodium acetate trihyd'rate in 2.5 liters of water. Duringthis addition the temperature of the mixture is kept below 10 C. and themixture is stirred.

The temperature of the stirred reaction mixture is allowed to rise toabout 20 C. The mixture is then acidified With concentrated hydrochloricacid.

A *solid product which has separated from the reatition mixture iscollected, washed with Water, and dried. An additional quantity of theproduct is obtained by saturating the combined filtrate and washingswith sodium chloride and then extracting four times with '600 ml. ofethyl acetate. The combined ethyl acetate extracts are dried with sodiumsulfate and concentrated under reduced pressure to a volume of about 350ml. One liter of petroleum ether is added to the warm concentrate. Thepetroleum ether-concentrate is then cooled in an ice bath. An additionalquantity of product crystallizes. The crystals are collected, 'dried,and added to the previous bath of N-(3-methyl-2-thenoylmethyl)acetamide.

The combined batches of N-(3-methyl-2-thenoylmeth yl)-acetamide may befurther purified, if desired, by recrystallization from aqueous ethanol.The product has the formula,

CHa

.S -CHzNHCO CH3 Solid sodium bicarbonate is added to a mixtureconsisting of 591 g. of N-(3-methyl-2-thenoylmethyl)acetamide, 1,100 ml.of water, and 452 ml. of 36-38% aqueous formaldehyde until the pH of themixture is about 7.5--& The reaction mixture is then stirred and heatedat a temperature of 35 C. for a period of about one hour. The mixture ispermittedfto cool to room temperature in about three hours. Then it iscooled thoroughly in an ice bath.

A precipitate of (dl) N [2 hydroxy1-(3-methyl-2-thenoyl)ethyl]acetamide, which has separated, is collected and washedwith a small amount of cold water and subsequently dried. The producthas the formula,

A solution of 3.8 g. of 95% sodium borohydride in of methanol is addedover a period of about 20 minutes to a mixture consisting of g. of(di)'-N-[ 2- hydroxy-l-(3-methyl-2-thenoyl) ethyllacetamide and 300 ml.of methanol. The temperature of the reactants is maintained at from 20to 25 C. by cooling the reactants with a water bath. The reactionmixture is stirred for a period of about fifteen minu'tes. The methanolis removed by distillation under reduced pressure.

The residual material is mixed with 250 ml. of water and warmed on thesteam bath for a period of about one-half hour. The resulting aqueoussolution is saturated with sodium chloride and extracted continuously ina liquid-liquid extractor with one liter of ethyl acetate. The ethylacetate extract is dried. The ethyl acetate is removed by distillationunder reduced pressure. The solid residue is triturated with 50 ml. ofether, collected, washed with ether and dried.

The product obtained in the above manner is a mixture of space isomersof 1-(3-methyl-2-thienyl)-2-acetamidol,3- 'propaned'iol and may berepresented by the following formula:

above may be acetylated in the following manner.

A mixture of 75 g. of (d2)-AB-1'-(3-methyl-2-thienyl)- Z-aCe'tam'ido-1,3propanediol is heated on a steam bath CHa I] 00003. IITHCOCH; /4511oH-omoooom The (dl)-A and (dl)-B forms may be separated at this stage byfractional crystallization from ethanol.

The above procedure may also be used for the acetylation of (dl)-A or(dl)-B-1-(3-methyl-2-thienyl)-2-acetamido-1,3-propanediol.

A mixture consisting of 13.6 g. of (dl)-B-l-(3-methyl- 2-thienyl)-2-acetamido 1,3 propanediol diacetate and 17.5 g. of acetic anhydrideis cooled to a temperature of about 5 C. To this mixture there is addedwith rapid stirring 4.3 g. of yellow fuming nitric acid (density=l.5)over a period of about 40 minutes. The temperature of the reactionmixture is maintained between and C. during the additon. Stirring iscontinued for an additional period of about one-half hour. The reactionmixture is then poured onto 100 g. of ice and the resulting mixtureneutralized by the addition of sodium bicarbonate.

The mixture neutralized with bicarbonate is extracted eight times with50 ml. of ethyl acetate. The combined ethyl acetate extracts are driedwith anhydrous magnesium sulfate. The ethyl acetate is removed bydistillation under reduced pressure. The residue consists mostly of(dl)-B-1-(3 methyl-S-nitro 2 thienyl)-2-acetamido-1,3- propanedioldiacetate and has the following formula:

OCOCH: NHCOCHa CH-- H-CHzO O 0 CH3 OaN- S (dl)-B form A mixtureconsisting of g. of the crude (dl)-B- l-(3-methyl-5-nitro-2-thienyl)-2-acetamido-1,3- propanedlol diacetate and100 ml. of 1.5 N hydrochloric acid is heated on a steam bath for aperiod of about one and one-half hours. The reaction mixture is thenconcentrated by distillation under reduced pressure (bath temperaturebelow 50 C.) to a volume of about 40 ml. The resulting concentrate iscooled in an ice bath and made alkaline (pH 9-10) by the addition of 6 Naqueous sodium hydroxide. The solid which precipitates is separated byfiltration, collected and washed with a small amount of cold water. a

The product consisting of (dl)-B-1-(3-methyl-5-nitro-2-thienyl)-2-amino-l,3-propanediol may be recrystallized if desired from amixture of ethylene dichloride-isoprov panol (3:1). Its formula is OHNH: O2N- S (JH(iIH-CH2OH v (dl)-B form A mixture consisting of 3.0 g. of(dl)-B-1-(3-methyl- '5-nitro-2-thienyl)-2-amino-1,3-propanediol and 25ml. of

methyl dichloroacetate is heated on a steam bath for a period of aboutone and one-half hours. The reaction mixture is cooled and extractedwith 100 ml. of petroleum ether. The residue is washed twice with 50 ml.of petroleum ether, and extracted with two 100 ml. portions of boilingethyl acetate.

The hot ethyl acetate extract is treated with decolorizing charcoal andfiltered. The ethyl acetate is then re moved from the filtrate bydistillation under reduced pressure. The residue is recrystallized fromaqueous ethanol to obtain the desired (dl)-B-l-(3-methyl5-nitro-2-thienyl)- 2 dichloroacetamido 1,3 propanediol. The compound soobtained has the formula,

OH NH0 0 01101:

OzN- S H- H-CHaOH Example 7 Preparation of (dl) -B-1-(5-nitro-2 thienyl)2 acetamido-1,3-propanediol:

A mixture consisting of l g. of (dl)-B-l-(S-nitro-Z-thienyl)-2-acetamido-1,3-propanediol diacetate (prepared as in Example1), 50 ml. of acetone, and 50 ml. of 0.2 N aqueous sodium hydroxide isstirred at a temperature of about 0 C. for a period of about one hour.The reaction mixture is then carefully neutralized with 6 N hydrochloricacid and the solution is concentrated to dryness under reduced pressure.The residue is extracted with hot ethyl acetate and the salt is removedby filtration. The ethyl acetate extract is then evaporated to drynessunder reduced pressure and the crystalline residue is recrystallizedfrom ethyl acetate. The product, (dl) -B-1-(S-nitro-Z-thienyl)-2-acetamido-1,3-propanediol (M. P. 1825-1835") hasthe following formula:

OH NHCOCH;

I l OzN S CH-OH-CHzOH (d!) -B form Analysis calculated for C9H12N2O5S:C, 41.53; H, 4.65; N, 10.76. Found: C, 41.62; H, 4.70; N, 10.54.

Example 8 Preparation of (dl) -B-1-(3-methyl 5-nitro-2-thienyl)-Z-acetamido-1,3-propanediol:

A mixture consisting of 1 g. of (dl)-B-1-(3-methyl-5-nitro-2-thienyl)-2-acetamido 1,3-propanediol (prepared as in Example 6),50 ml. of acetone and 50 ml. of 0.2 N sodium hydroxide solution isstirred at a temperature of about 0 C. for a period of about one hour.The reaction mixture is neutralized by addition of 6 N hydrochloricacid. I I

The neutralizedmixture is concentrated to dryness by distillation underreduced pressure. The residue is extracted with boiling ethyl acetateand the extract is filtered to remove the sodium chloride. The ethylacetate extract is evaporated to dryness under reduced pressure. Theresidue is recrystallized from aqueous ethanol. The product has theformula,

OH NHCO CH;

(dl) -B form Example 9 Preparation of (dl) B-l-(5-bromo-2-thienyl)2-thenamido)-1,3-propanediol:

1 g. of (al) -B-1-(5-bromo-2-thienyl)-2-amino-1,3-prcpanediol of Example2 is mixed with 25 ml. of ethyl acetate. 0.75 g. of 2-thenoyl chlorideis added, while the reaction mixture is maintained at a temperature ofabout 0 C. The resulting mixture is allowed to stand with occasionalstirring for a period of about one-half hour and then 25 ml. of water isadded. The ethyl acetate layer is removed and washed with dilutehydrochloric acid. so-

chloride. The product thus formed has the formula,

jir g'iii 25' diu'm bicarbonate solution, and'finll'y with water. Theethyl acetate is distilled off under reduced pressure and the residue isrecrystallized from aqueous ethanol. The product so obtained has theformula,

(dl)- B form Example Preparation of (dl) -B-1-(3-methyl-5-nitro 2thienyl)- 2- (alpha-chloropropionamido -1,3 -prop anediol:

To a mixture consisting of 1 g. of (dl)-B-l-(3-methyl-5-nitro-2-thienyl)-2-amino-l,3 propanediol (prepared as in Example 6),50 ml. of ethyl acetate and 50 ml. of 0.5 N sodium hydroxide solutionmaintained at about 0 C. there is added 1.5 ml. of alpha-chloropropionylchloride. The resulting "mixture is agitated at a temperature of 0 C.for a period of from about 10 to 15 'ir'iinute's.

The ethyl acetate layer is removed and the aqueous layer is extractedtwice with ethyl acetate. The combined ethyl acetate extracts arecollected and dried. The ethyl acetate is removed by distillation underreduced pressure. The residue is recrystallized from ethylene di- OHNHCOCHCICH: OzN- (EH-H-(EHzOH (am-B rom Example 11 Preparation of(dl)-l3-1-(5-nitro-2-thienyl) 2-benzamido-l,3-propanediol:

To a mixture consisting of 2 g. of (dl)-B-l-(S-nitro-Z- 4'0thienyl)-2-amino-1,3-propanediol (prepared as in Example 1), 10 g. 'ofmethylbenzoa'te and ml. of methanol there is added a methanolic solutionof sodium methoxide prepared by dissolving 0.16 g. of sodium in 15 ml.of methyl alcohol. The resulting mixture is heated at a temperature of95 C. for a period of about one-half hour. It is then diluted with 2%volumes of water and neutralized by the addition of dilute hydrochloricacid.

A gummy product is collected from the mixture. The product is purifiedby fecrystal'li'zations from ethyl acetate and ethanol. The purifiedproduct has the following formula:

H H-o'rno'rr (dl)-B form Example 12 Preparation of(dl)-B-l-(3-methyl-5-nitro-2-thienyl)-2- isobutyramido-l,31propanediol IA well-agitated mixture consisting of l g. of (dl)-B4- (3 methyl 5 nitro2 thienyl) 2 amino 1,3- propanediol (prepared as in Example 6) and 1 ml.of isobutyric anhydride. is 'heated at a temperature of about 95 C. fora period of about 8 minutes. The reaction mixture is then cooled in anice bath and the product, which separates, is collected andrecrystallized from ethyl acetate. The formula of the product soobtained is 0H NHCOGH(CHB)I OaN H l1 -OHz0 H (dl)-B form 26 Example 13Preparation of (dl)-B-1 (5 nitro 2 thienyl)2=(2,4-dichlorophenoxyacetamido l ,3-p'ropanediol A mixture consistingof 1 g. of (dl)-B-l-(5-nitro-2- thienyl)-2 'amino-1,3-propanediol(prepared as in Example 1) and 2 g. of methyl 2,4-dichlorophenoxyacetateis heated on the steam bath for a period of about two hours. Thereaction mixture is then cooled and extracted several times with 30 ml.portions of petroleum ether. The residue which failed to dissolve isextracted four times with boiling ethyl acetate. The combined ethylacetate extracts are dried with sodium sulfate and are then concentratedto dryness under reduced pressure. The residue contains a product havingthe following formula, and is recrystallized from absolute ethanol:

(dl)-B form Example 14 Preparation of (dl)-B-1-(S-nitro-Z-thienyl)-2-cyclohexanecarboxamido-1,3-propanediol 1 g.of cyclohexanecarboxylyl chloride is added to a cooled mixtureconsisting of l g. of (dl)-B-l-(S-nitro-Z- thienyl-2-amino-1,3-propanediol and 25 ml. of ethyl aceta'te. The resultingmixture is stirred and maintained at a temperature of about 0 C. for aperiod of about 12 minutes. 25 ml. of ethyl acetate is then added. Theresulting solution is washed with dilute hydrochloric acid, saturatedwith sodium bicarbonate solution, and finally with water.

The ethyl acetate solution is then dried and concentrated to dryness bydistillation under reduced pressure. The residue is recrystallized fromethyl acetate and has the formula,

(dl)-B form Example 15 Preparation of(dl)-B-1-(5-nitro-2-thienyl)-2-trifiuoroacetamido-1,3-propanediol:

A mixture consisting of 2.5 g. of (dl)-B-l-(5-nitro-2-thienyl)-2-amino-l,3-propanediol (prepared as in Example 1), 5.5 ml. ofethyl trifluoroacetate, and 35 ml. of methanol is heated under refluxfor a period of forty-five minutes. The resulting mixture isconcentrated to dryness by distillation under reduced pressure. Theresidue is extracted twice with 50 ml. portions of petroleum ether. Theundissolved residue is extracted with ml. of boiling ethyl acetate.

The ethyl acetate extract is treated with decolorizing charcoal,filtered, cooled, then washed successively with 5% hydrochloric acid,saturated aqueous sodium bicarbonate, and water. The extract is finallydried with anhydrous magnesium sulfate. The ethyl acetate is thenremoved by distillation under reduced pressure. The crystalline residue(M. P. l24.5126 C.) is chiefly the product which has the followingformula:

I on IIIHC o 0 F1 o,N- dn -orr-omorr (dl)-B form This product ispurified by recrystallization from ethylene dichloride which raised itsM. P. to 126.5l27 C.

Analysis calculated for CsHsFsNzOsS: C, 34.40; H, 2.89; N, 8.92. Found:C, 34.00; H, 3.22; N, 8.76.

Example 16 where R1 is a member of the class consisting of hydrogen andlower alkyl radicals R2 is am ember of the class consisting of hydrogen,halogen, nitro and lower alkyl radicals, and X is a member of the classconsisting of chloro and bromo radicals, with a mineral acid, to obtaina compound of the formula,

acylating the latter compound, recovering a compound of the formula,

Elfin? thus formed, reacting the latter compound with formaldehyde inthe presence of dilute alkali to obtain a compound of the formula l I lI IIIH-AcyI R S C-CH-CEzQH reacting the latter compound with sodiumborohydride, recovering a compound of the formula,

acylating the latter compound, recovering a triacyl compound of theformula,

R1 I I I C| -Acyl ITlH-Acyl Ra- S OHOHCHzO-Aoyl hydrolyzing the lattercompound with acid in an aqueous medium, neutralizing the acid withalkali, recovering a compound of the formula,

R1 I I on IITH: ni S CHCHCH2OH and mono acylating the latter compound toobtain a compound of formula,

I I I on IITH-Acyl R S dn-on-ornon 2. A process which comprises thesteps of hydrolyzing a compound of the formula,

CH:-/N I l I o /CH2 R ii onr-ri-onkN enur- CH2 CHTN where R1 is a memberof the class consisting of hydrogen and lower alkyl radicals, R2 is amember of the class consisting of hydrogen, halogen, nitro and loweralkyl radicals, and X is a member of the class consisting of chloro andbromo radicals, with a mineral acid, to obtain a compound of theformula,

I I I O I I R: S 0-0 Hi-NHTHCI reacting the latter compound with adichloroacetyl halide to obtain a compound of the formula I l I 0NE-COCHCI: R S g-AEH:

reacting the latter. compound with formaldehyde in the presence ofdilute alkali to obtain a compound of the formula,

reacting the latter compound with sodium borohydride, recovering acompound of the formula,

J I I on NH-ooonoh R S on-r n-omon acylating the latter compound,recovering a triacyl compound of the formula,

| I (I)-Acy1 NH-COCHCI; R s CH-J7HCHaO-Acyl hydrolyzing the lattercompound with acid in an aqueous medium, neutralizing the acid withalkali, recovering a compound of the formula,

r I I I OH NH, 3 S Julian-011,05

and mono acylating the latter compound to obtain a compound of formula,

l 'i I I on NH-Acyl R S H-(JH-CHQOH 3. A process of claim 5 in which thetriacyl compound of the formula,

29 Where R1 and acyl have the same significance as in claim 1, and R2 ishydrogen, is treated with fuming nitric acid and acetic anhydride toobtain a compound of the formula,

1 I l I O-Aeyl NH'Acyl 02N- s JHdH-Hl0-Ac 1 hydrolyzing the lattercompound with dilute acid, neutralizing the acid with alkali, recoveringa compound of formula,

1 I I OH NH: OnN S H-( /H:CH2OH and mono acylating the latter compoundto obtain a compound of formula,

L I I on NH-Acyl OaN S H-Ha-CHnOH 4. In a process, the steps comprisingreacting a compound of formula,

1 L I I o NH-Acyl a S ii-dn-omon where R1 is a member of the class ofhydrogen and lower alkyl radicals, R2 is a member of a class consistingof hydrogen, halogen, nitro and lower alkyl radicals, said acyl being acarboxylic acid acyl, with sodium borohydride to obtain a compound offormula,

ih I l I OH NH-Aeyl R2- S dH-JJH-GHiOH where R1, R2 and acyl have thesame significance as above.

5. In a process for obtaining (dl)B-1-(5-nitro-2-thienyl)-2-dichloroacetamido-1,3-propanediol, the steps comprisingreacting N-(Z-thenoylmethyl)hexamethylenetetraminium bromide with amineral acid in the presence of an alcohol, recovering the[(2-thenoyl)methyl]amine salt thus formed, reacting the latter compoundwith acetic anhydride in a dilute alkaline solution to obtain N-(2-thenoylmethyl)acetamide, reacting the latter compound so obtained withformaldehyde in a dilute alkaline solution, recovering the(dl)-N-[2-hydroxy-1-(2-thenoyl)- ethyllacetamide, reducing the lattercompound with sodium borohydride, recovering the isomeric mixture of1-(2-thienyl)-2-acetamido-1,3 propanediols, acetylating the lattermixture with acetic anhydride to obtain triacetyl derivatives of A- andB-I-(Z-thienyl)-2-amino-1,3- propanediols, hydrolyzing the lattermixture with water to obtain a mixture consisting of N,O-diacety1derivatives.

of (dl) -B-1-(2-thienyl)-2 amino 1,3 propanediol and (dl)-A-l-(2-thienyl)-2-amino-1,3-propanediol, recovering the higher meltingN,O-diacetyl derivative of (dl)-B-l-(Z-thienyl)-2-amino-1,3-propanediol, acetylating the latter compoundwith acetic anhydride to the(dl)-B-triacety1-1-(2thicnyl)-2-amino-1,3-propanediol, reacting thelatter racemic mixture with nitric acid and acetic anhydride, recoveringthe (dl)-B-1-(5-nitro-2-thienyl)-2-acetamido-l,3-propanediol diacetatethus formed, hydrolyzing the latter compound with mineral acid,neutralizing the acid with alkali, recovering the (dl)-B-l-(S-nitro-Z-thienyl)-2-amino-1,3-propanediol thus obtained, and reacting the latterproduct with methyl dichloroacetate to obtain(dl)-B-1-(5-nitro-2-thienyl-2 dichloroacetamido- 1,3-propanediol.

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1. A PROCESS WHICH COMPRISES THE STEPS OF HYDROLYZING A COMPOUND OF THEFORMULA,